A multidisciplinary effort will be made to design and synthesize a) an antineoplastic agent effective against slow growing tumors, and b) a radiosensitizing agent to sensitize tumor cells towards treatment with X-irradiation. Butylated hydroxytoluene (BHT), a free radical inhibitor, has been shown to possess some clinical utility in patients with bladder tumors. Attempts will be made to delineate the biochemical mechanism(s) of action of this agent, and to design and synthesize a series of BHT analogs to increase the antineoplastic activity. The agents synthesized in this program will be tested for antineoplastic activity in a wide spectrum of rodent neoplasms, particularly including slow growing solid tumors. The effects of these agents will also be studied on macromolecular synthesis and on cell membranes of tumor cells. Since both BHT and nitroimidazoles have been shown to sensitize tumor cells towards treatment with X-irradiation, efforts will be made to explore the structural requirements for selective sensitization of hypoxic cells present in solid tumors. These agents will be tested in vitro in bacterial as well as mammalian cell systems in tissue culture; experiments will also be conducted for in vivo radiosensitization. Active agents resulting from this program will be studied for pharmacokinetics, toxicity, biochemical mechanisms of drug action, and DNA repair mechanisms either after exposure to drug alone or in combination with ionizing radiation. The results of these experiments should provide the essential information to allow more rational use of a radiosensitizing agent in combination with radiation treatment to increase therapeutic efficacy.